Current treatment for Sickle cell disease (SCD) and beta thalassemia is, at best, symptomatic involving blood transfusions, the use of drugs to remove iron and to control pain, and in cases with HLA-compatible siblings, bone marrow transplantation. Our studies and others, have shown that in both disorders, high levels of fetal hemoglobin (Hb F, alpha1gamma2) have a major beneficial effect. The ability to produce Hb F in response to disease varies enormously from patient to patient, and is one of the major factors underlying the remarkable diversity in the severity of these disorders. This has prompted an intense search for approaches to augment fetal hemoglobin production in patients with SCD and beta thalassemia, one of which involves the use of drugs such as hydroxyurea and butyrate analogues. However, these agents are limited by their toxicity and they are effective in only a proportion of patients. The long term objective of this proposal is to obtain a better understanding of the genetic factors which modify fetal hemoglobin and F cell (FC) levels in normal adults and in response to disease. We have demonstrated for the first time that Hb F and F cell levels are highly heritable and transmitted as a complex genetic trait, influenced by several factors including a common sequence variant (C to T) in the Ggamma-promoter region, referred to as the Xmn1-Ggamma site. In earlier studies, as part of a systematic search for loci that may regulate gamma globin gene expression in beta thalassemia and SCD, we have identified an extensive kindred which includes individuals with beta thalassemia and hereditary persistence of fetal hemoglobin (HPFH). A quantitative trait locus (QTL) modifying fetal Hb production has been mapped to chromosome 6q23 in this kindred but variance components analysis revealed that a significant amount of FC variance remained unaccounted for. Furthermore, other QTLs for Hb F and FC have been implicated in different family studies. The presence of the Xmn1-Ggamma site is a major determinant for FC levels, and its location suggests that it is involved in transcriptional activation of the Ggamma globin gene. A linkage re-analysis of the genome-wide data in the kindred was carried out under a two-locus genetic model, with one of the loci being the Xmn1-Ggamma site. A new locus on chromosome 8q has now been identified using this method. Now, in an integrated program, we propose to isolate and characterize the 8q QTL by three approaches: (1) positional (candidate) gene cloning, (2) functional cloning by complementation assays in transgenic mice, and (3) differential gene expression analysis, in parallel with the 6q project. The delineation of these genetic factors should increase our understanding of the trans-acting factors for the fine tuning in the control of Hb F production after birth in normal adults and in response to disease with implications for pharmacogenomics. The discovery of these factors may also suggest new approaches for therapeutic augmentation of fetal hemoglobin production in patients with SCD and beta thalassemia.